Tonya Arscott-Mills

Treatment Failures and Excess Mortality Among HIV-Exposed, Uninfected Children With Pneumonia

BACKGROUND Human immunodeficiency virus (HIV)-exposed, uninfected (HIV-EU) children are at increased risk of infectious illnesses and mortality compared with children of HIV-negative mothers (HIV-unexposed). However, treatment outcomes for lower respiratory tract infections among HIV-EU children remain poorly defined. METHODS We conducted a hospital-based, prospective cohort study of N = 238 children aged 1-23 months with pneumonia, defined by the World Health Organization. Children were recruited within 6 hours of presentation to a tertiary hospital in Botswana. The primary outcome--treatment failure at 48 hours--was assessed by an investigator blinded to HIV exposure status. RESULTS Median age was 6.0 months; 55% were male. One hundred fifty-three (64%) children were HIV-unexposed, 64 (27%) were HIV-EU, and 20 (8%) were HIV-infected; the HIV exposure status of 1 child could not be established. Treatment failure at 48 hours occurred in 79 (33%) children, including in 36 (24%) HIV-unexposed, 30 (47%) HIV-EU, and 12 (60%) HIV-infected children. In multivariable analyses, HIV-EU children were more likely to fail treatment at 48 hours (risk ratio [RR]: 1.83, 95% confidence interval [CI]: 1.27-2.64, P = .001) and had higher in-hospital mortality (RR: 4.31, 95% CI: 1.44-12.87, P = .01) than HIV-unexposed children. Differences in outcomes by HIV exposure status were observed only among children under 6 months of age. HIV-EU children more frequently received treatment with a third-generation cephalosporin, but this did not reduce the risk of treatment failure in this group. CONCLUSIONS HIV-EU children with pneumonia have higher rates of treatment failure and in-hospital mortality than HIV-unexposed children during the first 6 months of life. Treatment with a third-generation cephalosporins did not improve outcomes among HIV-EU children.

Use of Xpert for the diagnosis of pulmonary tuberculosis in severely malnourished hospitalized Malawian children.

Background : Pulmonary tuberculosis contributes to increased morbidity and mortality in severely malnourished children in endemic settings. Despite high clinical suspicion, few tuberculosis prevalence estimates exist in malnourished African children. Diagnostics such as Xpert MTB/RIF may help to determine pulmonary tuberculosis prevalence, however its performance in severely malnourished children is largely unknown. Methods: We conducted a prospective observational study evaluating Xpert compared to smear microscopy and liquid culture on induced sputums among severely malnourished children (aged 6 to 60 months) at Kamuzu Central Hospital in Lilongwe, Malawi. From February 1 to May 30, 2012, children who met World Health Organization 2006 guidelines for severe acute malnutrition were evaluated using clinical symptoms, tuberculin skin tests, chest radiographs, and induced sputums. National Institute of Health (NIH) consensus case definitions were used to estimate tuberculosis prevalence. Results: Three hundred severely malnourished children (median age 18.5 months, IQR 12.1-25.6) had one induced sputum performed; 295 (98.3%) received two. Fifty-two (17.6%) were HIV-infected. Over 25% had tuberculosis exposure with 48/297 (16.2%) reporting contact and 40/287 (13.9%) with positive TST. Two (0.7%) patients had confirmed tuberculosis by Xpert and culture, but only one had positive smear microscopy. Twenty (6.7%) patients fulfilled probable and 97 (66%) met possible tuberculosis NIH case definitions. Overall mortality was 9.7%. Conclusions: Microbiologic confirmation likely underestimates the prevalence of pulmonary tuberculosis in severely malnourished children. In our study, Xpert on induced sputums did not increase case finding. Future studies are needed using Xpert among targeted groups of severely malnourished children and on non-sputum specimens.

Association of Respiratory Viruses with Outcomes of Severe Childhood Pneumonia in Botswana

Background The highest incidence of childhood acute lower respiratory tract infection (ALRI) is in low- and middle-income countries. Few studies examined whether detection of respiratory viruses predicts ALRI outcomes in these settings. Methods We conducted prospective cohort and case-control studies of children 1-23 months of age in Botswana. Cases met clinical criteria for pneumonia and were recruited within six hours of presentation to a referral hospital. Controls were children without pneumonia matched to cases by primary care clinic and date of enrollment. Nasopharyngeal specimens were tested for respiratory viruses using polymerase chain reaction. We compared detection rates of specific viruses in matched case-control pairs. We examined the effect of respiratory syncytial virus (RSV) and other respiratory viruses on pneumonia outcomes. Results Between April 2012 and August 2014, we enrolled 310 cases, of which 133 had matched controls. Median ages of cases and controls were 6.1 and 6.4 months, respectively. One or more viruses were detected from 75% of cases and 34% of controls. RSV and human metapneumovirus were more frequent among cases than controls, but only enterovirus/rhinovirus was detected from asymptomatic controls. Compared with non-RSV viruses, RSV was associated with an increased risk of treatment failure at 48 hours [risk ratio (RR): 1.85; 95% confidence interval (CI): 1.20, 2.84], more days of respiratory support [mean difference (MD): 1.26 days; 95% CI: 0.30, 2.22 days], and longer duration of hospitalization [MD: 1.35 days; 95% CI: 0.20, 2.50 days], but lower in-hospital mortality [RR: 0.09; 95% CI: 0.01, 0.80] in children with pneumonia. Conclusions Respiratory viruses were detected from most children hospitalized with ALRI in Botswana, but only RSV and human metapneumovirus were more frequent than among children without ALRI. Detection of RSV from children with ALRI predicted a protracted illness course but lower mortality compared with non-RSV viruses.

Yield of contact tracing from pediatric tuberculosis index cases in Gaborone, Botswana.

SETTING Contact tracing using pediatric index cases has not been adequately investigated in high tuberculosis (TB) and human immunodeficiency virus (HIV) prevalence settings. OBJECTIVE To determine the yield of contact tracing in household contacts of pediatric TB index cases in Botswana. DESIGN Index cases included all pediatric (age ≤ 13 years) TB admissions from January 2009 to December 2011 to Botswanas largest referral hospital. A contact tracing team identified cases, conducted home visits, symptom-screened contacts and referred those with ≥ 1 TB symptoms. The primary outcome was newly diagnosed TB in a contact. RESULTS From 163 pediatric index cases, 548 contacts were screened (median 3 contacts/case, interquartile range [IQR] 2-4). Of these, 49 (9%) were referred for positive symptoms on screening and 27/49 (55%) were evaluated for active TB. Twelve new TB cases were diagnosed (12/548, 2.2%); the median age was 31 years (IQR 23-38); 11 (92%) were smear-positive. Ten (83%) had known HIV status: 7 (70%) were HIV-positive. To find one new TB case, the number needed to contact trace (index cases/new cases) was 13.6, and the number needed to screen (contacts/new cases) was 46. CONCLUSION This yield of contact tracing using pediatric index cases is similar to the traditional adult index case approach. Improving the proportion of symptomatic contacts evaluated may increase yield.

Hospital-based surveillance for rotavirus gastroenteritis using molecular testing and immunoassay during the 2011 season in Botswana.

We describe rotavirus testing and clinical characteristics for children admitted with acute gastroenteritis during Botswanas 2011 rotavirus season. The rotavirus season extended from June to October with rotavirus-specific case fatality being 2.8%. Using molecular testing as reference, the immunochromatographic test had a sensitivity of 76.5% and specificity of 68.0%. Rotavirus vaccine may significantly reduce childhood morbidity and mortality in Botswana.

Chest Radiographic Findings and Outcomes of Pneumonia Among Children in Botswana.

Background: Chest radiography is increasingly used to diagnose pneumonia in low-income and middle-income countries. Few studies examined whether chest radiographic findings predict outcomes of children with clinically suspected pneumonia in these settings. Methods: This is a hospital-based, prospective cohort study of children 1–23 months of age meeting clinical criteria for pneumonia in Botswana. Chest radiographs were reviewed by 2 pediatric radiologists to generate a consensus interpretation using standardized World Health Organization criteria. We assessed whether final chest radiograph classification was associated with our primary outcome, treatment failure at 48 hours, and secondary outcomes. Results: From April 2012 to November 2014, we enrolled 249 children with evaluable chest radiographs. Median age was 6.1 months, and 58% were male. Chest radiograph classifications were primary endpoint pneumonia (35%), other infiltrate/abnormality (42%) or no significant pathology (22%). The prevalence of endpoint consolidation was higher in children with HIV infection (P = 0.0005), whereas endpoint pleural effusions were more frequent among children with moderate or severe malnutrition (P = 0.0003). Ninety-one (37%) children failed treatment, and 12 (4.8%) children died. Primary endpoint pneumonia was associated with an increased risk of treatment failure at 48 hours (P = 0.002), a requirement for more days of respiratory support (P = 0.002) and a longer length of stay (P = 0.0003) compared with no significant pathology. Primary endpoint pneumonia also predicted a higher risk of treatment failure than other infiltrate/abnormality (P = 0.004). Conclusions: Chest radiograph provides useful prognostic information for children meeting clinical criteria for pneumonia in Botswana. These findings highlight the potential benefit of expanded global access to diagnostic radiology services.

Rural exposure during medical education and student preference for future practice location - a case of Botswana

Background Botswana’s medical school graduated its first class in 2014. Given the importance of attracting doctors to rural areas the school incorporated rural exposure throughout its curriculum. Aim This study explored the impact of rural training on students’ attitudes towards rural practice. Setting The University of Botswana family medicine rural training sites, Maun and Mahalapye. Methods The study used a mixed-methods design. After rural family medicine rotations, third- and fifth-year students were invited to complete a questionnaire and semi-structured interview. Data were analysed using descriptive statistics and thematic analysis. Results The thirty-six participants’ age averaged 23 years and 48.6% were male. Thirty-three desired urban practice in a public institution or university. Rural training did not influence preferred future practice location. Most desired specialty training outside Botswana but planned to practice in Botswana. Professional stagnation, isolation, poorly functioning health facilities, dysfunctional referral systems, and perceived lack of learning opportunities were barriers to rural practice. Lack of recreation and poor infrastructure were personal barriers. Many appreciated the diversity of practice and supportive staff seen in rural practice. Several considered monetary compensation as an enticement for rural practice. Only those with a rural background perceived proximity to family as an incentive to rural practice. Conclusion The majority of those interviewed plan to practice in urban Botswana, however, they did identify factors that, if addressed, may increase rural practice in the future. Establishing systems to facilitate professional development, strengthening specialists support, and deploying doctors near their home towns are strategies that may improve retention of doctors in rural areas.

The Nasopharyngeal Microbiota of Children with Respiratory Infections in Botswana.

Background: Nearly half of child pneumonia deaths occur in sub-Saharan Africa. Microbial communities in the nasopharynx are a reservoir for pneumonia pathogens and remain poorly described in African children. Methods: Nasopharyngeal swabs were collected from children with pneumonia (N = 204), children with upper respiratory infection symptoms (N = 55) and healthy children (N = 60) in Botswana between April 2012 and April 2014. We sequenced the V3 region of the bacterial 16S ribosomal RNA gene and used partitioning around medoids to cluster samples into microbiota biotypes. We then used multivariable logistic regression to examine whether microbiota biotypes were associated with pneumonia and upper respiratory infection symptoms. Results: Mean ages of children with pneumonia, children with upper respiratory infection symptoms and healthy children were 8.2, 11.4 and 8.0 months, respectively. Clustering of nasopharyngeal microbiota identified 5 distinct biotypes: Corynebacterium/Dolosigranulum-dominant (23%), Haemophilus-dominant (11%), Moraxella-dominant (24%), Staphylococcus-dominant (13%) and Streptococcus-dominant (28%). The Haemophilus-dominant [odds ratio (OR): 13.55; 95% confidence interval (CI): 2.10–87.26], the Staphylococcus-dominant (OR: 8.27; 95% CI: 2.13–32.14) and the Streptococcus-dominant (OR: 39.97; 95% CI: 6.63–241.00) biotypes were associated with pneumonia. The Moraxella-dominant (OR: 3.71; 95% CI: 1.09–12.64) and Streptococcus-dominant (OR: 12.26; 95% CI: 1.81–83.06) biotypes were associated with upper respiratory infection symptoms. In children with pneumonia, HIV infection was associated with a lower relative abundance of Dolosigranulum (P = 0.03). Conclusions: Pneumonia and upper respiratory infection symptoms are associated with distinct nasopharyngeal microbiota biotypes in African children. A lower abundance of the commensal genus Dolosigranulum may contribute to the higher pneumonia risk of HIV-infected children.

The effect of exposure to wood smoke on outcomes of childhood pneumonia in Botswana

SETTING Tertiary hospital in Gaborone, Botswana. OBJECTIVE To examine whether exposure to wood smoke worsens outcomes of childhood pneumonia. DESIGN Prospective cohort study of children aged 1-23 months meeting clinical criteria for pneumonia. Household use of wood as a cooking fuel was assessed during a face-to-face questionnaire with care givers. We estimated crude and adjusted risk ratios (RRs) and 95% confidence intervals (CIs) for treatment failure at 48 h by household use of wood as a cooking fuel. We assessed for effect modification by age (1-5 vs. 6-23 months) and malnutrition (none vs. moderate vs. severe). RESULTS The median age of the 284 enrolled children was 5.9 months; 17% had moderate or severe malnutrition. Ninety-nine (35%) children failed treatment at 48 h and 17 (6%) died. In multivariable analyses, household use of wood as a cooking fuel increased the risk of treatment failure at 48 h (RR 1.44, 95%CI 1.09-1.92, P = 0.01). This association differed by child nutritional status (P = 0.02), with a detrimental effect observed only among children with no or moderate malnutrition. CONCLUSIONS Exposure to wood smoke worsens outcomes for childhood pneumonia. Efforts to prevent exposure to smoke from unprocessed fuels may improve pneumonia outcomes among children.

Risk factors for gastric aspirate culture contamination in children evaluated for tuberculosis in Botswana

SETTING Gastric aspirate (GA) sample culture is commonly performed in children evaluated for tuberculosis (TB) who cannot expectorate sputum. Contamination limits culture yield and negatively impacts care. OBJECTIVE To evaluate the proportion of and factors associated with GA contamination at a central TB reference laboratory in Botswana. DESIGN This was a 5-year cross-sectional study of untreated children aged 12 years evaluated for TB with the first GA sample registered at the National Tuberculosis Reference Laboratory. We performed descriptive statistics to assess the risk of contamination with patient age, sex, transport time and distance, culture medium, and facility type. We generated multivariable logistic regression models using generalized estimating equation extension. RESULTS We analyzed 3642 samples. The median age was 2 years (interquartile range [IQR] 1-4), median transport time was 4 days (IQR 2-7), and 64.1% of samples were from clinics or health posts. TB culture positivity was 1.6% (60/3642), and contamination was observed in 35.6% (1298/3642). Hospital collection was associated with lower contamination risk (adjusted OR [aOR] 0.53, 95%CI 0.40-0.69) and Mycobacteria Growth Indicator Tube vs. Löwenstein-Jensen medium with higher risk (aOR 1.88, 95%CI 1.51-2.34). CONCLUSION In routine care settings, high sample contamination and low TB culture yield were observed. This raises questions about the collection technique and storage in lower-level facilities and affirms higher risk with a liquid culture medium.